How can I be sure that the patient has noncirrhotic portal hypertension?

Portal hypertension is characterized by an increase in portal pressure (>10 mmHg) and could be a result of cirrhosis of the liver or noncirrhotic diseases. Noncirrhotic portal hypertension (NCPH) consists of a group of diseases; of intrahepatic or extrahepatic etiology, where hepatic venous pressure gradient (HVPG) is normal (<5 mmHg) or only marginally raised and is significantly lower than the portal vein pressure. In most of the diseases that are grouped under the category of NCPH (see subsection "Classification and causes of noncirrhotic portal hypertension" below), portal hypertension is a late manifestation of the disease.

Noncirrhotic portal fibrosis (NCPF) and extrahepatic portal vein obstruction (EHPVO) are two diseases that are common in developing countries and most often present only with features of portal hypertension and not of parenchymal dysfunction (Figure 1). These diseases are described in detail in this chapter.

How can I confirm the diagnosis?

This disease is distinctly different from cirrhosis of the liver. Earlier described as Banti's disease, tropical splenomegaly syndrome or Bengal splenomegaly, or hepatoportal sclerosis, it is more popularly known as idiopathic portal hypertension (IPH), or non-cirrhotic portal fibrosis (NCPF) (Figure 2).

NCPF or IPH has been reported in all parts of the world, more so in developing countries. It is believed to account for nearly one-sixth of all cases of variceal bleeding. The condition is seen commonly in people who are socio-economically disadvantaged. Improved hygiene and standards of living could explain the rarity of the disease in the West and its declining incidence in Japan. Although the acronyms NCPF and IPH often have been used interchangeably, the former is more common in men, seen in younger age, without presence of auto-antibodies, and has a good long-term prognosis.

Etiopathogenesis

Several hypotheses have been proposed, the most important being infective hypothesis. Abdominal infection and diarrheal episodes at birth or in early childhood are likely to lead to portal pyemia and pylephlebitis, which could result in thrombosis, sclerosis, and obstruction of small- and medium-sized portal vein radicals. In experimental studies, IPH, like changes in the liver and the development of portal hypertension, has been reported after injecting dead nonpathogenic colon bacilli into the portal vein of rabbits and dogs.

In another model of indwelling cannulation of the gastrosplenic vein, repeated injections of Escherichia coli resulted in the development of splenomegaly and an increase in portal pressure at 3 months.

Prolonged ingestion of arsenic in the drinking water or exposure to vinyl chloride, copper sulfate (vineyard sprayers), protracted treatment with methotrexate, hypervitaminosis A, have been incriminated in the causation of NCPF. It is thus likely that the liver behaves in a similar manner to various insults, which results in a near similar phenotype of NCPF.

Pathology

Often, the liver is normal, but it can be irregular or finally nodular in about 10% of cases. Progression from IPH to incomplete septal cirrhosis may occur in advanced stages. Generally, the portal vein is dilated with thickened and sclerosed walls. Autopsy series commonly show thrombosis in the medium and small (diameter <300 mm) portal vein branches. Histopathology of liver suggests that NCPF is primarily a venous disease – an obliterative portovenopathy – of the liver. The initial thickening of the intrahepatic portal venous channels, which is associated with obliteration of small portal venules and emergence of new aberrant portal channels, is quite characteristic of NCPF. Evidence of previous phlebothrombosis is suggested by the presence of old mural thrombi that are incorporated in the wall, mural thickening of the extrahepatic portal vein, and coexistence of lesions that are characteristic of NCPF and EHPVO in the same patient.

A widening of the space of Disse with haphazardly arranged collagen bands in the perisinusoidal space that leads to capillarization of sinusoids may be seen on electron microscopy. These changes suggest that the disease process in NCPF if diffuse.

Hemodynamics

NCPF, like cirrhosis, is a classical type of portal hypertension with a hyperdynamic circulatory state. The portal vein pressures and intravariceal correlate and are markedly elevated in NCPF – the latter being the investigation of choice to measure portal pressure. There are two pathoanatomic sites of obstruction: a pressure gradient between the spleen and the liver (intrasplenic pressure [ISP]–intrahepatic pressure [IHP]) and another exists between the IHP and the wedged hepatic venous pressure (WHVP; IHP–WHVP). Generally, the HVPG is normal or only slightly elevated in NCPF (
Figure 3). Splenic and portal vein blood flow are known to be increased markedly in Japanese patients who have IPH, which is suggestive of a hyperdynamic circulatory state.

Clinical features

The patients commonly present with one or more well-tolerated episodes of gastrointestinal hemorrhage, a long-standing mass in the left upper quadrant (splenomegaly), and consequences of hypersplenism. Development of ascites, jaundice, and hepatic encephalopathy is uncommon and may be seen only after an episode of gastrointestinal hemorrhage.

Over a 22-year period (1983-2004), the author saw 307 patients who had NCPF, whereas EHPVO was diagnosed in 499 patients. The demographic profile of these patients is shown in Table I.

Table I. Clinical profile of patients with EHPVO

Parameters

%

Mean age (yrs)

19.4

Sex (M/F)

1:0.5

Hematesis/malena

77%

Mass LUQ

20%

Transient ascites

23%

Jaundice

23%

Esophageal varices

93%

Portal gastropathy

60%

Portal biliopathy

90%

Laboratory features

Patients with NCPF have preserved hepatic functions with normal serum albumin and INR. Anemia is common, and it can be microcytic, hypochromic (due to gastrointestinal blood loss), or normocytic, normochromic (due to hypersplenism). Leukopenia (<4000 cells/mm3) and thrombocytopenia (150,000 cells/mm3) are not uncommon. Although, asymptomatic hypersplenism is common, symptomatic hypersplenism is rare in NCPF.

Coagulation and platelet function anomalies also have been observed in patients who have NCPH. Mild compensated disseminated intravascular coagulation secondary to endotoxemia or portosystemic collaterals has been reported in a fair proportion of these patients. The frequency of hepatitis B and C in nontransfused patients who have NCPF is not higher than that seen in the general population. Autonomic dysfunction has been well documented in cirrhosis. It also has been reported in NCPF, which suggests some contribution of portal hypertension because liver functions are near normal in NCPF.

Imaging

Ultrasonography is the investigation of choice. It shows a dilated and patent splenoportal axis with significantly thickened walls of the portal vein and its main branches. This is quite consistent with the initial description of hepatoportal sclerosis that was given to this disease. Doppler studies are helpful in identifying an occasional patient who has a thrombus in the intrahepatic branch of the portal vein. Spontaneous splenorenal shunts are seen in 10% to 15% of NCPF patients – more frequently than seen in cirrhotics. CT portography and CT hepatic angiography also have been recommended to distinguish between NCPF and cirrhosis.

Portal biliopathy. Portal biliopathy, defined as anomalies of the biliary system and gall bladder in patients who have portal hypertension, is seen commonly in patients who have EHPVO. It also is not uncommon in patients who have NCPF and cirrhosis.

Endoscopy

Esophagogastric varices are seen in 85% to 95% of patients who have NCPF. Furthermore, patients who have NCPH have large varices more often (90%) compared with cirrhotic patients (70%). Anorectal varices also are more common (90% vs. 56%) and are bigger in size. Gastric varices are also more common in NCPF than in cirrhosis. Portal hypertensive gastropathy is uncommon and is a rare cause of upper gastrointestinal (UGI) bleed at the first presentation in patients who have NCPF.

What other diseases, conditions, or complications should I look for in patients with noncirrhotic portal hypertension?

Differential diagnoses

The diagnosis of NCPF is easy. Child's A cirrhosis may be confused with NCPF; however, the tests of liver function, viral serology, and histology (lobular disarray, pseudolobule formation) and, above all, a normal HVPG can clearly distinguish between the two. Whereas a disproportionately large spleen with a dilated and thickened portal vein favors the diagnosis of NCPF, it may not be easy to differentiate it from chronic EHPVO with recanalized portal vein. Tropical splenomegaly syndrome is another condition in the tropics that presents with massive splenomegaly; however, portal hypertension is uncommon in these patients. Moreover, elevated serum IgM levels and high malarial antibody titers are common in tropical splenomegaly syndrome.

What is the right therapy for the patient with noncirrhotic portal hypertension?

Management

Management of acute and recurrent variceal bleeding and hypersplenism are the main concerns in patients who have NCPF. For acutely bleeding varices, variceal band ligation and endoscopic sclerotherapy are equally efficacious (approximately 95% success in control of acute bleed). Both techniques also are quite effective in achieving variceal obliteration with a low variceal recurrence rate of about 20%. Prevention of rebleeding with the use of nonselective b-blockers has been reported by our group to be equally effective as endoscopic variceal ligation. We have also reported that b-blocker and endoscopic variceal ligation are equally efficacious for primary prophylaxis in NCPH patients. Gastric varices, which are more common in NCPF, can be managed with cyanoacrylate glue injection and rarely require surgical intervention.

Interventional radiologic procedures have been reported to be effective in patients who have IPH. These include splenic artery embolization, percutaneous transhepatic obliteration, and a transjugular intrahepatic portosystemic shunt (TIPS) procedure.

The role of surgery is limited in variceal bleed because it is required in less than 5% of cases of NCPF that fail to respond to endoscopic therapy. Selective shunts, like distal splenorenal shunts, are preferred because they have a lower incidence of postshunt encephalopathy; however, if massive splenomegaly is present, the proximal shunt with splenectomy is a good choice. Surgery also is indicated for patients who have symptomatic hypersplenism, for patients who hail for distant areas, or for those who desire on-time treatment. Development of membranoproliferative glomerulonephritis and other renal anomalies have been reported following shunt surgery in patients who have NCPF.

Prognosis

The prognosis of patients who have NCPF is good. The mortality from an acute bleed in NCPF is significantly lower than that observed in cirrhotic patients. After successful eradication of esophagogastric varices, the author has observed almost 100% 2- and 5-year survival in these patients. The long-term outcome of shunt surgery also is favorable and 88% 5-year survival has been reported. Shunt occlusion, postshunt encephalopathy, and renal dysfunction may cause some morbidity.

What is the most common cause of noncirrhotic portal hypertension?

Extrahepatic portal vein obstruction

Extrahepatic portal vein obstruction (EHPVO) is defined as obstruction of the extrahepatic portal vein without involvement of the intrahepatic portal veins or splenic or superior mesenteric veins. Isolated occlusion of the splenic vein or superior mesenteric vein does not constitute EHPVO. Earlier, the term "portal vein thrombosis" (PVT) often was loosely interchanged with EHPVO, but in both Baverno IV and V, EHPVO has been accepted as the preferred term. This is mainly to exclude the intrahepatic PVT that is due to cirrhosis of the liver or invasion by hepatocellular carcinoma.

Epidemiology: EHPVO is a common cause of portal hypertension in developing countries but is less prevalent in the West where it is the second most common cause of portal hypertension (even in the West). In the West, EHPVO accounts for 5% to 10% of all cases of portal hypertension, but in developing countries, this proportion is higher and may reach 15% to 20%. In children, EHPVO accounts for 80% to 90% of cases of portal hypertension. In children, EHPVO usually is an isolated condition and is only recognized when the child develops symptoms. In adults, the diagnosis is made earlier because most of the patients are under observation for another disease. Most commonly, blockage occurs at the site of the portal vein formation (90%); total blockage of the splenoportal axis is seen in only 10% of cases.

Etiology: The etiology of EHPVO (subsection "Causes of extrahepatic portal vein obstruction," below) is not very clear and varies considerably with age and the geographic region.

In children

Infection. Omphalitis and neonatal umbilical sepsis, umbilical vein cannulation for exchange transfusion, and repeated abdominal infections leading to portal pylephlebitis with thrombosis are the most likely causes. Abdominal surgery in childhood, trauma, and dehydration have also been suggested. Rarely also could congenital anomalies of the portal vein be responsible.

Presence of an underlying prothrombotic state, both in children and in adults, is among the most common underlying condition. However, there are limited studies of thrombophilic disorders in children.

In adults

There is increasing evidence that prothrombotic disorders are seen more commonly in patients who have EHPVO. Thrombophilic conditions are seen in 60% of PVT patients, while local predisposing factors account for 30%. Usually, there is more than one factor responsible for PVT.

Latent or overt myeloproliferative disorders have been the most documented causes. An acquired mutation (JAK 2/V617F) testing associated with presence of myeloproliferative disorders (MPD) yields a higher rate of diagnosis. JAK2 gene mutation is presently considered among the major criteria in MPD. In one study, the risk for EHPVO was found increased in the presence of thrombophilia resulting from the prothrombin G20210A mutation and from the deficiencies of the naturally occurring anticoagulant proteins but not from factor V Leiden. A simple method of screening deficiency of natural anticoagulants in patients with liver disease comprises of the ration of protein S (PS) or protein C (PC) or antithrombin III (AT) to [(Factor II + Factor X/2)]. If the result is less than 70%, a genetic cause needs to be evaluated.

Inherited and acquired prothrombotic states

Inherited and acquired prothrombotic states responsible for PVT are given below.

Acquired

(MPD)

Antiphospholipid syndrome

PNH

OCT and pregnancy

Hyperhomocysteinemia

Inherited

Factor V Leiden mutation

Prothrombin mutation

Factor S and factor C deficiency

The role of infection in EHPVO in adults is limited to intra-abdominal sepsis; a thrombotic stimulus (e.g., pregnancy, oral contraceptives) and the presence of underlying prothrombotic disorders may be causative.

In an adult who has EPHVO, the possibility of underlying cirrhosis and hepatocellular carcinoma needs to be excluded. PVT is an important complication of cirrhosis, with incidences of between 0.6% and 16% in patients who have well-compensated disease. An increased frequency is seen in those who have decompensated disease and in up to 35% of cirrhotic patients who have hepatocellular carcinoma, in whom the thrombosis also may be due to extension of the tumor.

In patients who have an identified cause, general thrombophilic factors account for 60% of cases and local factors account for 40%. In a large proportion of patients, the cause of adult EHPVO remains obscure, however.

"Sinistral" or left-sided portal hypertension, with localized thrombosis of the splenic vein, occurs in 7% of patients who have chronic pancreatitis. PVT also follows splenectomy in 6% to 8% of cases.

Pathology: Mild or sometimes moderate hepatic fibrosis is seen in up to 40% of adult patients, partly as a result of prolonged reduced portal blood supply to the liver. Vascular lesions have been demonstrated in approximately 48% of cases in the form of multiple portal vein channels in small portal tracts, in addition to mild portal fibrosis in a majority. The portal vein shows cavernous malformation and is made up of a cluster of variable-sized vessels that are arranged haphazardly within a connective tissue support, and the original portal vein cannot be identified.

Pathophysiology: The prehepatic block of EHPVO with normal hepatic sinusoidal pressure and a high pressure in the obstructed splanchnic bed results in the formation of multiple hepatopetal thick, winding collaterals. These collaterals are seen on angiography as cavernous transformation and were shown by ultrasound Doppler studies to provide a significant component of the total hepatic blood flow in patients. These collaterals join the intrahepatic portal vein branches at various levels. This is a kind of neovascularization to compensate for the portal vein block.

Impairment of the hepatic storage capacity and transport maximum for bromsulphathaline has been documented. The portal vein obstruction, reduced portal blood flow, and increased dependence of the liver on hepatic arterial blood in EHPVO may contribute to a decreased functional status of the liver.

Clinical presentation and course: The clinical presentation varies according to the age, duration, and extent of PVT.

– Recent EHPVO. This could be entirely asymptomatic or present with varied degrees of severity of clinical symptoms and signs. These could include severe noncholic abdominal pain, distention, fever, or mild ascites. Ileus should raise suspicion of intestinal infarction. Portal pylephlebitis should be suspected if spiky fevers, tenderness, shock, and sepsis-related cholestasis are seen.

– Chronic EHPVO. EHPVO generally presents in childhood or adolescence with repeated episodes of hematemesis without significant decompensation. Colorectal lesions are seen in approximately two-thirds of patients with portal hypertension. Two types of colonic lesions have been described in patients with portal hypertension, namely, anorectal varices and colopathy. Bleeding form ectopic varices (e.g., duodenum, biliary tree, and gallbladder) is not uncommon in these patients.

Anemia and moderate to massive splenomegaly are the other common presentations in children who have EHPVO. Occasionally, patients present with severe left upper quadrant pain due to splenic infarction or perisplenitis. Ascites may manifest in about 10% to 20% of children following hemorrhage or surgery. Persistent ascites requiring diuretics is seen in about 20% of adult patients and reflects deterioration of liver function with decrease in serum albumin levels.

Patients may present with features of obstructive jaundice due to portal biliopathy. It refers to abnormalities of the extrahepatic and intrahepatic bile ducts without anomalies of the gall bladder wall in patients who have portal hypertension (Figure 4). The changes include indentations of paracholedochal collaterals on the bile duct; localized strictures; angulation of ducts; displacement of ducts and stones in the common bile duct; and focal narrowing dilations, irregular walls, and clustering of intrahepatic branches in the hepatic ducts.

Gall bladder varices are common and carry a significant amount of blood around the gall bladder. The frequency of gallstones is higher in patients who have EHPVO. Although biliopathy is seen in 80% to 100% of cases, only a few patients are symptomatic. Symptomatic patients usually are adults, which indicates that portal biliopathy is a progressive disease. Complications such as cholangitis, secondary biliary cirrhosis, gall stones, hemobilia, hypoalbuminemia, and coagulation disturbances have been reported.

Generally, growth retardation is seen when EHPVO develops before puberty. Growth patterns in patients who have EHPVO indicate that nearly one-third is short in stature and has significantly diminished growth velocity. This could be a result of deprivation of the portal blood that has hepatotrophic factors in it. Growth spurts have been observed after shunt surgery in patients who have EHPVO. The author has seen more than 650 patients of EHPVO in children. The clinical and demographic profile of these patients is shown in Table I.

Hemodynamics: The hepatic vein pressure gradient is normal and intrasplenic pressure is significantly elevated, which indicate the presinusoidal nature of the block. Intravariceal pressure is the ideal method for measuring the portal pressure in patients who have NCPH. Total hepatic blood flow is normal or decreased; however, hepatic arterial flow is increased after portal venous obstruction. Systemic vascular resistance is significantly lower and cardiac output is significantly higher in patients who have EHPVO.

What is the most effective initial therapy?

Diagnosis of extrahepatic portal vein obstruction

The presence of esophageal varices in a child with normal or near-normal liver function tests should raise the possibility of EHPVO. In an adult, compensated cirrhosis may produce a similar picture. Recent EHPVO may be symptomatic or even asymptomatic. Therefore, the diagnosis may be difficult and a high index of suspicion is needed. Ultrasound is precise for the detection of portal cavernoma, which is seen as a distinctive tangle of tortuous vessels in the porta hepatis. An ultrasound Doppler is, however, more helpful to detect a recently formed thrombus that is virtually anechoic and splenoportal collaterals and shunts (Figure 5). Contrast enhanced CT, CT arterial portography, and MR angiography also have a high degree of sensitivity and specificity (Figure 6). Liver biopsy is helpful whenever there is suspicion of any parenchymal liver involvement.

Once the diagnosis of EHPVO is established, it is important that investigations to unearth the pathogenesis of EHPVO be undertaken. Tests for confirming the overt or the occult myeloproliferative disorders, risk factors for venous thromboembolism (e.g., factor V Leiden mutation, G20210A, prothrombin gene mutation, and levels of proteins C and S and antithrombin III) also can be helpful. MRI of the abdomen and MRCP help the detection of portal biliopathy.

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

N/A

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

N/A

Listing of these, including any guidelines for monitoring side effects.

N/A

How should I monitor the patient with extrahepatic portal vein obstruction?

How do I manage extrahepatic portal vein obstruction?

The management of EHPVO needs to be tailored according to the age of the patient, the site of obstruction, and the clinical manifestations.

Recent EHPVO

Symptomatic recent EHPVO rarely resolves spontaneously in noncirrhotic patients. Low molecular weight heparin should be started immediately followed by oral anticoagulant therapy. In asymptomatic patients, anticoagulation should also be considered. Anticoagulation should be given for at least 3 months, unless an underlying persistent prothrombotic state has been documented; in which case, prolonged anticoagulation is recommended. Rapid thrombolysis or removal of the thrombus through the transjugular route is also a reasonable option. Antibiotic therapy should be given if there is any evidence of SIRS or infection.

Chronic EHPVO

Acute and recurrent variceal hemorrhage should be managed with endoscopic variceal ligation. For primary prophylaxis of variceal bleeding, there is insufficient data on whether beta blocker or endoscopic therapy should be preferred. For secondary prophylaxis, endoscopic therapy is effective and there is evidence to suggest that beta blockers are as effective as EVL.

Symptomatic hypersplenism or painful splenic lump merits splenectomy or splenic artery embolization. Shunt surgery is reserved for patients who fail endoscopic therapy or have significant growth retardation before puberty, symptomatic portal biliopathy, and symptomatic hypersplenism. It also can be offered to patients who demand a "one-time" treatment. Rex shunts (mesenterico-left portal bypass) in children who have EHPVO are effective and are considered to be more physiologic because they restore normal portal flow to the liver. Symptomatic portal biliopathy, if due to choledocholithiasis; should be managed with endoscopic sphincterotomy. The risk of recurrent stone disease, cholangitis, and secondary biliary cirrhosis continue. It is the next most common cause of death after variceal bleeding in patients who have EHPVO.

The role of anticoagulant therapy in chronic EHPVO is not clear and only can be considered if there is a history of recurrent thrombotic episodes and after shunt surgery. It is not clear whether anticoagulant therapy can increase the risk for gastrointestinal bleeding or the severity of bleeding.

Portal vein thrombosis in cirrhotics before and after liver transplant poses additional problems. Due to hepatocellular injury in these patients, more thrombin is generated – which causes intrahepatic thrombosis. A recent French study used the prophylactic anticoagulants in chronic liver disease patients with portal vein thrombosis who were waiting for transplants and found good results post transplant. After liver transplantation, PVT is seen in about 1% to 2% of cases in the early period, with preferential localization to the anastomotic site.

In summary, patients who have NCPH pose special challenges to clinicians. It is worthwhile to know the spectrum of presentation, rational diagnostic tests, and appropriate management of these patients.